1. Field of the Invention
This invention pertains to the field of collagen membrane matrices. More specifically, the present invention relates to collagen membranes having physical and biological properties which make them extremely suitable and desirable for all types of medical uses, particularly as a periodontal barrier. Methods for preparing these membranes and applications for their use are also disclosed.
2. Discussion of Related Art
Collagen has been used extensively in medicine and in surgery. Collagen is a fibrous protein and constitutes the major protein component of skin, bone, tendon, ligament, cartilage, basement membrane and other forms of connective tissue. It is the most abundant protein in the animal kingdom. In bone, for example, collagen fibers reinforce the calcium phosphate mineral base. Despite its great strength, bone retains flexibility because of its collagen content.
Collagen based devices have been used as nerve regeneration tubes, as sutures, hemostatic fiber and sponges, wound dressings, neurosurgical sponges, injectable implants for soft tissue augmentation, pharmaceutical carriers, opthalmic aqueous-venous shunts, contact lenses and the like.
The properties of collagen which favor its use as a biomaterial are many. It has a high order of tensile strength and low extensibility. Collagen is biodegradable, and when implanted in the body, is absorbed at a rate that can be controlled by the degree of intra or intermolecular cross-linking imparted to the collagen molecule by chemical or physical treatment. Collagen products can thus be designed such that, on implantation, they will completely be absorbed in a few days or in months. The collagen can also be chemically treated so that it becomes non-absorbable while still retaining its hydrophilic character and its good tissue response. Although native collagen is a very weak antigen, it can be made, for all practical purposes, immunologically inert by means well known to those skilled in the art.
The collagen molecule is a triple helix and has a unique protein configuration that is a coiled coil of three polypeptide subunits or alpha chains. Each alpha chain twists in a left-handed helix with three residues per turn, and three chains are wound together in a right-handed superhelix to form a rod-like molecule about 1.4 nanometers in diameter and 300 nanometers long. The alpha chains each contain about 1,050 amino acid residues and the molecular weight of the collagen molecule is about 300,000. In each alpha chain within the triple helix every third amino acid residue is glycine. Collagen is characterized by a high content of proline and hydroxyproline amino acids, the absence of tryptophane, a minor amount of aromatic amino acids, and a significant amount of dicarboxylic and dibasic amino acids. At both ends of the collagen molecule there are terminal peptide sequences known as telopeptides which are globular and not triple helical in structure and which lack glycine at every third residue. These telopeptides are the primary sites of inter-molecular cross-linking in the molecule and are the most antigenic portions of the collagen molecule.
The collagen molecule which is elaborated by fibrogenic cells aggregate in the extracellular matrix of connective tissue to form fibrils which range from 10 to 200 nanometers in diameter. The collagen fibrils aggregate into collagen fibers.
The main sources of collagen for commercial applications are bovine tendons, calf, steer or pig hide. All are readily available at relatively low cost. Generally, reconstituted collagen products are prepared by purification of native collagen by enzyme treatment and chemical extraction. The purified collagen is then dispersed or dissolved in solution, filtered and retained as such, or is reconstituted into fiber, film or sponge by extrusion or casting techniques which are well known to those skilled in the art.
Although the collagen of skin, tendons, bone, cartilage, blood vessels and basement membrane are similar in structure and composition, they do differ slightly in relative amino acid content, amino acid sequence and in architecture. They are products of different genetic loci. The different genetic collagens are known as Type I, II, III, IV, V, etc. The collagen of native skin, tendons, ligaments and bone are primarily Type I collagen with which the present invention is directed.
Generally, regardless of the particular genetic collagen that is utilized, when in the form of a dry film, it will typically be transparent and have a morphology which has a feel not unlike that of a thin sheet of plastic. When wetted, the collagen film material, in addition to being transparent, now becomes slippery and slimy as well. While such a transformation may have little, if any, effect upon the performance of the collagen film material when it has already been affixed in position for its intended use prior to such transformation, it may create numerous problems and disadvantages if such transformation takes place prior to such utilization, which is generally the case. Thus, in many instances, it is necessary for the physician or dentist to work with the collagen film material in a manner such that it will readily contour itself to the surface upon which it is being applied. For example, when utilizing a collagen film as a wound covering, the dry and relatively rigid membrane will not easily conform to the wound and its shape without first being wetted. Once wetted, the collagen film will easily conform to the shape of the wound being treated. However, the transparency and slipperiness of the collagen film makes it extremely difficult for the doctor to properly handle and see, particularly when a relatively small wound area is being treated. This is even further made difficult when, as is conventionally done, the collagen film is to be sutured.
Such a disadvantage is particularly noticeable when a collagen film is utilized as a periodontal barrier. More specifically, with advanced periodontal disease, after the root surface has been surgically exposed and debrided, it is desirable to place a membrane over these areas and then have the mucoperiosteal flaps adapted over such membrane and sutured. The membrane helps prevent epithelim and gingival connective tissue from contacting the root of the tooth during healing, thereby allowing the area to be repopulated with cells originating from the periodontal ligament. This is the basis for what is known in the art today as "guided tissue regeneration." However, in order to be so utilized, if the membrane is made of collagen in the form of a rigid film, it must first be wetted causing it to be not only transparent but also slippery and slimy as well. In view of the small area that needs to be covered with this film as a periodontal barrier, the transparency, sliminess and slipperiness of this material makes it extremely difficult, if not practically impossible, for the user to handle. Still further, the transparency and morphology of the wetted collagen film material makes it extremely difficult to ascertain that the film is properly positioned in the surgical site making it a less than an ideal material for periodontal surgery.
Moreover, the rate of resorption of a collagen film material in the body may not always be easily controllable to the extent desired such that resorption occurs when most advantageous, particularly in periodontal surgery. In such applications, it is desirable to have an intact collagen film for a predetermined period of time after implantation, to be subsequently resorbed at a faster rate. However, the resorption of conventional collagen films generally starts and remains at the surface which is in contact with the body inasmuch, as we have found, the pore size of such collagen films does not readily permit enzymes to penetrate into the inner layers of the film to allow for uniform, controlled resorption.
The use of a collagen membrane as a periodontal barrier is described in, for example, "The Use of Collagen Membranes to Guide Regeneration of New Connective Tissue Attachment in Dogs" by Neil M. Blumenthal, Journal of Periodontology, Volume 59, No. 12, pgs. 830-836 (1988). While other membrane materials have been utilized as periodontal barriers, such as Teflon membranes, as discussed in, for example, "New Attachment Formation in the Human Periodontium by Guided Tissue Regeneration" by Jan Gottlow, et al., Journal of Clinical Periodontology, 13:604-616 (1986) and "New Attachment Achieved by Guided Tissue Regeneration in Beagle Dogs" by R. G. Caffesse, et al., Journal of Periodontology, Volume 59, No. 9, pgs. 589-594, such other materials suffer from the major disadvantage of not being resorbable by the body. Instead, these alternative materials must be removed by yet a second surgical procedure.
A need accordingly exists for a collagen material, particularly a collagen membrane, which does not become slippery, slimy and transparent when wetted. A need also exists for such a collagen material to have a relatively constant, predetermined controlled density which facilitates in vivo resorption. Still further, it would also be desirable to have a collagen membrane with a predetermined, relatively constant permeability, i.e., a pore size, which will be particularly amenable to allowing specific constituents through the membrane, such as nutrients, enzymes and macromolecules, while effectively preventing the diffusion of undesirable constituents, such as fibrogenic cells. In conjunction with these needs, the collagen material still needs to have excellent mechanical strength and controlled high resorptivity. Such needs are particularly desirable in the field of periodontology.